Diversity oriented synthesis of pyrrolidines via natural carbohydrate solid acid catalyst

Article abstract of DOI:10.1021/cc100007a

Natural carbohydrate scaffold catalyzed diastereoselective synthesis of functionalized pyrrolidines have been developed via 1,3-dipolar cycloaddition of azomethine ylides derived from α-imino esters with dienes or dipolarophiles. Naturally most abundant carbohydrates, like cellulose and starch, were converted into their sulfuric acid derivative, which are exhibiting efficient catalytic properties, along with excellent cost effectivity and recyclability. The advantages of this methodology are diversity oriented metal free synthesis of functionalized pyrrolidines, mild reaction condition, high diasteroselectivity and yield.

Full text of DOI:10.1021/cc100007a

458
J. Comb. Chem. 2010, 12, 458–462
Diversity Oriented Synthesis of Pyrrolidines via Natural Carbohydrate
Solid Acid Catalyst
Atul Kumar,* Garima Gupta, and Suman Srivastava
Medicinal and Process Chemistry DiVision, Central Drug Research Institute, Lucknow, India
ReceiVed January 15, 2010
Natural carbohydrate scaffold catalyzed diastereoselective synthesis of functionalized pyrrolidines have been
developed via 1,3-dipolar cycloaddition of azomethine ylides derived from R-imino esters with dienes or
dipolarophiles. Naturally most abundant carbohydrates, like cellulose and starch, were converted into their
sulfuric acid derivative, which are exhibiting efficient catalytic properties, along with excellent cost effectivity
and recyclability. The advantages of this methodology are diversity oriented metal free synthesis of
functionalized pyrrolidines, mild reaction condition, high diasteroselectivity and yield.
Pyrrolidines are an important class of heterocycles found
ylides with R,ꢀ-unsaturated ketones or aryl nitroethylenes
to generate substituted pyrrolidines. Che et al. have developed
ruthenium porphyrins catalyzed diastereoselective synthesis
of substituted pyrrolidine from R-diazoester with N-ben-
zylidene imines and alkenes.12 Interestingly, Jørgensen et.
al13 reported cinchona alkaloids and silver fluoride catalyzed
in numerous natural products,1 bioactive molecules,2 orga-
nocatalysts,3 and building blocks in organic synthesis.1b,4
(Figure 1). In our ongoing research toward the development
of diversity oriented synthesis of biologically important
heterocycles,5 we report here diversity-oriented, metal-free
synthesis of biologically relevant heterocyclic pyrrolidine
scaffolds. In comparison to target-oriented synthesis (TOS),
in which the plan is to access precise or dense regions of
chemistry space, diversity-oriented synthesis (DOS) popu-
lates chemical space mostly with small-molecules having
diverse structures and is now considered to be an important
tool for lead identification in the area of drug discovery.
The objectives of DOS involve development of pathways
leading to the efficient synthesis of collections of small
molecules having skeletal and stereochemical diversity with
defined coordinates in chemical space. Chemical genetics
may benefit from collections of small molecules that are both
structurally complex and diverse.6 Structural diversity is
crucial for lead generation in chemical genetics and drug
discovery.7 Diversity-oriented synthesis is a tool to discover
new areas of chemical space efficiently. It can be argued
that more diverse starting points for lead optimization are
presenting scaffolds with superior selectivity profile, com-
pared to narrowly defined chemical libraries.8 Consequently
the efficient construction of pyrrolidine molecules has
received significant attention. 1,3-Dipolar cycloaddition of
azomethine ylide and dipolarophile is the method of choice
for the synthesis of diversity-oriented pyrrolidines or proline
derivatives.
Table 1. Comparison of CellSA and StarSA in the Synthesis of
Pyrrolidinesa
entry catalyst
R
diene R1 time (h) yield (%)b endo (%)c
1
2
3
4
5
6
CellSA 2-NO2
StarSA 2-NO2
CellSA 3-F
StarSA 3-F
CellSA 2-Br
StarSA 2-Br
2a
2a
2a
2a
2a
2a
Et
Et
Et
Et
Et
Et
30
32
28
30
24
24
70
66
90
75
75
56
100
76
98
72
95
70
a Reaction conditions: Aromatic R-imino ester 1 (1 mmol), dienes or
dipolarophiles 2 (1 mmol), CellSA or StarSA (0.03 g), ethanol (2-3
mL), rt. b Isolated yield. c Determined by the 1H NMR spectroscopic
analysis.
Table 2. Cellulose Sulfuric Acid Catalysed Synthesis of
Substituted Pyrrolidinesa
entry
R
dienes R1 time (h) yield (%)b endo (%)c
1
2
3
4
5
6
7
8
H
4-F
2a1
2a1
2a1
2a
2a
2a
2a
2a
2a
2a
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
28
30
24
36
25
30
24
28
24
24
26
24
28
34
29
30
30
34
32
80
90
85
65
85
70
75
90
75
80
70
75
75
85
80
55
85
92
85
90
95
85
95
92
100
100
98
95
95
90
85
95
90
90
80
95
95
95
2-Me
4-MeO
4-F
2-NO2
3-NO2
3-F
9
2-Br
10
11
12
13
14
15
16
17
18
19
4-PhCH2O
4-N(CH3)2
2-Cl
2a
2a
Et
Et
Recently, several regio- and diastereoselective synthesis
of substituted pyrrolidines via cycloaddition of azomethine
ylides have been reported. Scheidt et.al. reported copper(I)
salt-catalyzed three-component reaction between an R-diazo
ester, an imine, and various alkenes or alkynes with excellent
to good diastereoselectivity.9 Patzel et al.10 and Toke et al.11
used AgOAc, LiBr in presence of base, using azomethine
H
2a2
2b
2b
2b1
2c
2d
2d
Me
Me
Me
Me
Me
Et
4-MeO
4-Br
H
H
H
4-Cl
Et
a Reaction conditions: aromatic R-imino ester 1 (1 mmol), dienes or
dipolarophiles 2 (1 mmol), CellSA (0.03 g), ethanol (2-3 mL), rt. b Iso-
lated yield. c Determined by the 1H NMR spectroscopic analysis.
* To whom correspondence should be addressed. Tel.: 91-522-2612411.
Fax: 91-522-2623405. E-mail: dratulsax@gmail.com.
10.1021/cc100007a  2010 American Chemical Society
Published on Web 04/26/2010

Synthesis of Pyrrolidines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 459
Figure 1. Some important pyrrolidine scaffolds.
Figure 2. Natural supramolecular carbohydrate acid catalysts.
synthesis of pyrrolidines. All these methods involve metals
as catalyst for the synthesis of pyrrolidine derivatives.
We wish to report here a metal-free, diastereoselective and
diversity-oriented synthesis of substituted pyrrolidines using
cellulose sulfuric acid/starch sulfuric acid as a solid catalyst
from R-imino esters and dipolarophiles via 1,3-dipolar
cycloaddition.
Figure 3. CellSA optimization plot. Reaction conditions: N-(3-
fluorobenzylidene)-glycine ethyl ester (1 mmol), maleimide (1
mmol), CellSA (0.01-0.05 g), ethanol (2-3 mL), rt.
Figure 4. CellSA reusability plot. Reaction conditions: N-(3-
fluorobenzylidene)-glycine ethyl ester (1 mmol), maleimide (1
mmol), CellSA (0.03 g), ethanol (2-3 mL), rt, 28 h.

460 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Scheme 1. CellSA-Catalysed Synthesis of Subsituted Pyrrolidines
Kumar et al.
The two most abundant natural supramolecular carbohy-
drates (NSCar), cellulose and starch molecules are used for
catalytic purposes because they are biodegradable, very cost-
effective, and renewable resources. To achieve effective
catalytic properties, cellulose and starch were converted to
their sulfuric acid derivatives (Figure 2).
Cellulose sulfuric acid (CellSA) has an excellent catalytic
properties, which are attributed to the high thermal stability
and strong acid sites of sulfo functional groups. Cellulose is
more appropriate as a support compared to starch because
of poor solubility and high stability. CellSA has shown better
reusability than starch sulfuric acid (StarSA) for four
successive reactions under similar reaction condition without
any significant loss in the product yield. In addition, the
CellSA-catalyzed reaction has better yield and diastereose-
lectivity than StarSA for the synthesis of pyrrolidines (Table
1). Thus cellulose sulfuric acid was found to be more efficient
catalyst in comparison with starch sulfuric acid for the one-
pot synthesis of pyrrolidines.
catalyzed reactions, such as the synthesis of R-aminonitriles,
imidazoazines,14 and tetrahydroquinolines.15
Cellulose sulfuric acid is responsible for the protonation
of R-imino ester to give azomethine ylide and catalyzes the
cycloaddition. The cyclized product is obtained by the
reaction of the azomethine ylide generated from R-imino
ester 1 and olefinic dipolarophile 2 (1:1) in the presence of
cellulose sulfuric acid in ethanol via stirring at room
temperature (Scheme 1).
The reaction is highly diastereoselective and generates
endoisomer as predominant product. The stereochemistry of
1
the cycloadduct was determined by H NMR analysis.
The cellulose sulfuric acid (CellSA) was prepared follow-
ing a previously reported procedure.14,15 First cellulose
(DEAE for column chromatography, Sigma-Aldrich) in
absolute ethanol was treated with chlorosulfonic acid in a
slow dropwise addition. The solid obtained was washed with
acetonitrile to give cellulose sulfuric acid as white powder.
The powder was dried to obtain a fixed weight and used as
catalyst after analysis. The number of H+ site of CellSA
determined by acid-base titration and found to be 0.50
Recently, cellulose sulfuric acid (CellSA) has emerged as
a promising biopolymeric solid support acid catalyst for acid-
Figure 5. Azomethine ylides.

Synthesis of Pyrrolidines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 461
in short reaction time (6-7 h) with moderate diastereose-
lectivity (60% endo product was obtained). To explore 1,3-
dipolar cycloaddition and to generate diversity, a number of
R-imino esters (Figure 5) were cyclized with different
dipolarophiles (Figure 6) in good yields and high diastereo-
selectvities (only the endo products were observed) (Table
2).
Figure 6. Dienes or dipolarophiles (2).
A plausible mechanism for cycloaddition reaction is shown
in Figure 7. R-Imino ester coordinates to CellSA, and the
azomethine ylide-CellSA complex is generated by proton-
ation of R-imino ester-CellSA complex. The azomethine
ylide-CellSA complex reacts with dipolarophile to form
diastereoselective pyrrolidine (Figure 7).
In summary, we have developed a novel, metal free,
diastereoselective and diversity-oriented synthesis of sub-
stituted pyrrolidines catalyzed by cellulose sulfuric acid as
natural carbohydrate solid acid catalyst. This process involves
avoidance of harsh reaction condition, ecofriendly chemistry,
reusable catalyst, high diastereoselectivity, and high yield.
mequiv/g. This value corresponds to about 0.96% of the
sulfur content, indicating that most of the sulfur species are
in the form of sulfuric acid groups.
The reactions of R-imino esters with olefinic dipolarophiles
goes with high levels of diastereoselectivity regardless of
the electronic property of the aromatic ring. However
presence of a chloro or bromo substituent at the ortho
position of R-imino esters accelerated the reaction as reaction
completed in almost 24 h (Table 2, entries 9 and 12), whereas
lower reactivity was observed when a methoxy group is
present at para position of R-imino esters (reaction took place
in more than 30 h) (Table 2, entries 4 and 14). The different
imino esters reacted smoothly with maleimide and showed
high endoselectivity. Acrylates also gave endoadducts as the
major products, whereas slightly low reactivity observed with
aromatic nitroalkenes may be caused by steric hindrance of
aryl ring (reaction completed in more than 30 h) (Table 2,
entries 18 and 19).
The catalyst loading was optimized by taking N-(3-
fluorobenzylidene)-glycine ethyl ester and maleimide as an
model reaction in ethanol at rt. Reaction took place in 28 h
with 0.03 g of catalyst loading and almost 90% yield was
obtained (Table 2, entry 8). Lowering the catalyst loading
to 0.01-0.02 g results in 75-80% yield of pyrrolidine with
a longer reaction time of more than 40 h, whereas increasing
the concentration of catalyst has no significant effect on the
yield of the reaction (Figure 3).
One of the advantages of solid acid catalysts is their
reusability. Reusability of catalyst was checked under same
reaction condition as given above, that is, N-(3-fluoroben-
zylidene)-glycine ethyl ester and maleimide were reacted in
ethanol. After completion of reaction, as given in Table 2,
entry 8, cellulose sulfuric acid was recovered from the
reaction mixture by simple filtration, washed properly with
acetone, and dried in oven for 3 h at 70 °C prior to its use
in the absence of fresh catalyst. It was observed that catalyst
displayed quite good reusability at least four additional times
in subsequent reactions under the same reaction conditions
without any significant loss in productivity (Figure 4).
We have also studied the effect of temperature on reaction
rate. Increasing the reaction temperature to 70-80 °C results
Experimental Section
Preparation of Cellulose or Starch Sulfuric Acid. To a
magnetically stirred mixture of 5.00 g of cellulose (DEAE
for column chromatography, Sigma-Aldrich) or starch (Mer-
ck) in 20 mL of absolute ethanol, 1.00 g of chlorosulfonic
acid (9 mmol) was added dropwise at 0 °C over 2 h. HCl
gas escaped from the reaction vessel immediately. After the
addition was complete, the mixture was stirred for an
additional 2 h. After that, the mixture was filtered and washed
with 30 mL of acetonitrile and dried at room temperature to
obtain 5.20 g of cellulose sulfuric acid as white powder or
5.06 g of starch sulfuric acid as cream powder.
General Procedure for the Synthesis of r-Imino Esters.
A suspension of glycine methyl or ethyl ester hydrochloride
(1.1 equiv), excess MgSO4, and NEt3 (1.1 equiv) in CH2Cl2
was stirred at rt for 1 h. The aldehyde (1.0 equiv) was added,
and the reaction mixture stirred at rt overnight. The MgSO4
was removed by filtration, and the filtrate was washed
properly with water. The aqueous phase was extracted with
CH2Cl2, and the combined organic layers were washed with
brine. The organic phase was dried over Na2SO4, filtered,
and concentrated to give R-imino esters in good yield.
General Procedure for 1,3-Dipolar Cycloaddition. A
typical formation of pyrrolidines was carried out by reacting
R-imino ester 1 (1 mmol) with olefinic dipolarophile 2 (1
mmol) and 0.03 g of catalyst (CellSA) in ethanol (2-3 mL)
under stirring at room temperature. The reaction mixture was
stirred until completion of the reaction as evidenced by TLC.
Figure 7. Proposed mechanism of 1,3-dipolar cycloaddition.

462 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Kumar et al.
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CC100007A